High-dose melphalan with 6-hydroxydopamine–purged autologous bone marrow transplantation for poor-risk neuroblastoma

Abstract

Long-term results are presented of 28 patients who were diagnosed with neuroblastoma at more than 12 months of age and who received melphalan 180 mg/m2 (n = 6) or 240 mg/m2 (n = 22) to consolidate remissions of Stage IV disease or to control refractory disease. Twenty-four patients also received dianhydrogalactitol 180 to 240 mg/m2, and 11 received total body irradiation 450 to 600 cGy. Autologous bone marrow transplantation (ABMT) was performed with marrow that was unpurged (n = 2) or purged ex vivo (n = 26) with 6-hydroxydopamine (6-OHDA) 20 micrograms/ml plus ascorbate 200 micrograms/ml. The median time to an absolute neutrophil count of 500/microliters was 21 days and to self-sustaining platelet counts more than 20,000/microliters, 28 days. One patient required infusion of unpurged reserve marrow. Two groups of patients underwent ABMT: (1) 17 patients (Group I) who were in first remission a median of 7 months after diagnosis; and (2) 11 patients (Group II) who had refractory disease or were in second remission. For Group I, event-free survival was 29% at 12 months and 6% at 24 months post-ABMT. All Group II patients died of disease or ABMT-related toxicity. Overall, of the 28 patients, one is a long-term relapse-free survivor; five died of ABMT-related toxicity; ten patients with tumors present at ABMT had progressive disease within 6 months of ABMT; and 12 patients with no measurable disease at ABMT relapsed 4 to 32 months (median, 12) post-ABMT. Among the latter, six relapses involved the primary site, and six were restricted to distant sites. These results--in accord with the long-term outcome in other series--suggest that for neuroblastoma high-dose melphalan cannot be relied on to ablate residual disease or to salvage patients with refractory tumors. In addition, the pattern of relapse in several patients could be explained by infusion of incompletely purged autografts; this would support recent laboratory evidence that 6-OHDA/ascorbate is a suboptimal purging method.

Lack of survival advantage with autologous stem-cell transplantation in high-risk neuroblastoma consolidated by anti-GD2 immunotherapy and isotretinoin

“…Our group adopted ASCT consolidation of HR-NB in the 1980s based on the concept that high-dose alkylators can overcome chemoresistance [ 10 , 11 ]. Subsequently, after promising results with high-dose cyclophosphamide in induction [ 12 ], as well as with 3F8 in phase I and II trials [ 13 , 14 ], we undertook a non-ASCT study using dose-intensive induction followed by consolidation with 3F8 [ 15 ] and local RT [ 16 ].…”

Autologous Stem-Cell Transplantation for High-Risk Neuroblastoma: Historical and Critical Review

“…In the 1980s and 1990s, studies in neuroblastoma suggested an improvement of outcome with myeloablative therapy in conjunction with autologous BM transplant [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. It was the time when adult oncology was massively testing HDT strategies for solid tumors as previously reviewed.…”

6-fluorodopamine selectively destroys neuroblastoma cells expressing the noradrenaline transporter

“…6-Hydroxydopamine (6-OHDA) was used in combination with ascorbic acid for ex vivo purging of bone marrow stem cells from neuroblastoma cells before autologous bone marrow transplantation [1]. Autoxidation of 6-OHDA leads to the formation of cytotoxic reactive oxygen species (ROS), and this process is enhanced in the presence of an excess of ascorbic acid by redoxcycling [2].…”